Abstract

Stem cells have been successfully employed for the treatment of critical limb ischemia (CLI). We conducted a clinical trial to determine the feasibility of using autologous adipose-derived MSCs (AdMSCs) for the treatment of CLI. Unexpectedly, two diabetic patients developed peripheral microthrombosis. This adverse effect, which contrasts with the reported anti-thrombotic properties of MSCs, may stem from the diabetic environment that alters the fibrinolitic activity of AdMSCs thereby increasing the probability of developing thrombosis. Herein, we confirm this premise by demonstrating that diabetic AdMSCs cultured in the presence of blood sera expressed and released higher levels of plasminogen activator inhibitor type 1 (PAI-1), reduced levels of tissue plasminogen activator (tPA) and lower D-dimer formation as compared to non-diabetic AdMSCs. Thus to establish an appropriate cell therapy for diabetic patients, we recommend including new preclinical safety tests such as the D-dimer and/or tPA/PAI-1 ratio tests in order to assess fibrinolytic activity of cells prior to implantation.